Clinical and experimental data demonstrate unequivocally that hypertension accelerates atherosclerosis. This is an intriguing pathogenic phenomenon since the interaction is quite unambiguous for two complex diseases marked by clinical and genetic heterogeneity. Currently, the mechanisms underlying this interaction have not been elucidated. Strategic animal models are needed to mechanistically dissect pathogenesis. We have developed a transgenic hyperlipidemia- genetic hypertensive rat model by hepatic over-expression of human cholesteryl ester transfer protein (hCETP) in Dahl salt-sensitive (S) rats. Transgene high copy number in Tg[hCETP]53 Dahl S rats elicits aortic, coronary and intramyocardial atherosclerotic lesions and decreased life spans compared with no lesions in non-transgenic Dahl S controls and minor medial changes in Tg[hCETP]25 Dahl S rats with transgene moderate copy number. In this research proposal, we will investigate whether synergistic decrease of NO activity induced by both hypertension and atherosclerosis results in enhanced activated endothelial molecular and cellular changes which are then differentially amplified. as enhanced pro-inflammatory and pro-thrombotic changes leading to progressive vascular disease. The following specific aims will be studied: 1) Determined whether the endothelium of hypertensive, markedly hyperlipidemic Tg[hCETP]53 Dahl S rats exhibit exaggerated endothelial cell activation (marked by enhanced and/or sustained up- regulation of ICAM-1 and P-selectin gene expression and increased monocyte adhesion compared with control age-matched normotensive, markedly hyperlipidemic Tg[hCETP]53 Dahl salt-resistant (R) male rats, and control non-transgenic age-matched hypertensive, normolipidemic Dahl S rats. 2) Determine whether exaggerated activation results in amplified dysregulation through enhanced pro-inflammatory response (marked by increased TNF-alpha expression and increased NF-kappaB activation in endothelial cells, macrophages) and/or pro-thrombotic response (marked by tissue factor TF expression in endothelial cells, macrophages, intimal smooth muscle cells)--distinct from corresponding arteries in control normotensive, markedly hyperlipidemic Tg[hCETP]53 Dahl R rats as well as in control hypertensive, normo-lipidemic Dahl S rats. 3) Define the hierarchical relationship of hypertension hyperlipidemia and decreased NO activity on the acceleration of atherosclerosis by determining which manipulation, high salt diet, Western Type Diet, or NO-inhibitor L-NA treatment will cause Tg[hCETP]25 Dahl S rats to exhibit similar atherosclerotic lesion phenotype similar to Tg[hCETP]53 Dahl S rats. 4) Define the mechanistic role of endothelial NO pathway in the interaction of hypertension and atherosclerosis; sufficient versus essential but not sufficient versus modifying but not essential by early, mid-point, and late-onset L-arginine treatment of Tg[hCETP]53 Dahl S rats and determine whether the acceleration of atherosclerosis by hypertension is differentially attenuated, if not significantly resolved. This research proposal will provide key information on mechanisms that underlie the acceleration of atherosclerosis by hypertension which will identify new strategies for intervention.